U.S. patent application number 11/855521 was filed with the patent office on 2008-04-17 for dipyrazole compounds and their use as central nervous system agents.
This patent application is currently assigned to AVENTIS PHARMACEUTICALS INC.. Invention is credited to Raymond W. KOSLEY, Douglas MACDONALD, Rosy SHER.
Application Number | 20080090872 11/855521 |
Document ID | / |
Family ID | 36617194 |
Filed Date | 2008-04-17 |
United States Patent
Application |
20080090872 |
Kind Code |
A1 |
KOSLEY; Raymond W. ; et
al. |
April 17, 2008 |
DIPYRAZOLE COMPOUNDS AND THEIR USE AS CENTRAL NERVOUS SYSTEM
AGENTS
Abstract
The present invention is directed to dipyrazole compounds of
formula I and their pharmaceutically acceptable salts,
stereoisomers, tautomers, or solvates thereof. Novel compounds
include those of formula I. ##STR1## The compounds of this
invention modulate AMPA and NMDA receptor function, and therefore
are useful as pharmaceutical agents, especially for the treatment
of neuropsychiatric disorders.
Inventors: |
KOSLEY; Raymond W.;
(Bridgewater, NJ) ; MACDONALD; Douglas; (Los
Angeles, CA) ; SHER; Rosy; (Bridgewater, NJ) |
Correspondence
Address: |
ANDREA Q. RYAN;SANOFI-AVENTIS U.S. LLC
1041 ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
AVENTIS PHARMACEUTICALS
INC.
55 Corporate Boulevard
Bridgewater
NJ
08807
|
Family ID: |
36617194 |
Appl. No.: |
11/855521 |
Filed: |
September 14, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2006/009348 |
Mar 15, 2006 |
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11855521 |
Sep 14, 2007 |
|
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60662195 |
Mar 16, 2005 |
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Current U.S.
Class: |
514/326 ;
514/404; 514/407; 546/211; 548/365.4 |
Current CPC
Class: |
C07D 231/22 20130101;
A61P 43/00 20180101; A61P 25/28 20180101; A61P 25/00 20180101; A61P
25/08 20180101; C07D 231/26 20130101; A61P 25/24 20180101; C07D
401/14 20130101; A61P 25/18 20180101 |
Class at
Publication: |
514/326 ;
514/404; 514/407; 546/211; 548/365.4 |
International
Class: |
A61K 31/4155 20060101
A61K031/4155; A61K 31/4468 20060101 A61K031/4468; A61P 25/00
20060101 A61P025/00; A61P 25/18 20060101 A61P025/18; A61P 25/24
20060101 A61P025/24; C07D 401/14 20060101 C07D401/14; C07D 403/04
20060101 C07D403/04 |
Claims
1. A compound of formula I: ##STR56## wherein: R.sub.1 is selected
from the group consisting of aryl, benzyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl, C.sub.3-8cycloalkylC.sub.1-6alkyl, hetero-aryl,
arylcarbonyl, arylC.sub.1-6alkylC.sub.3-8cycloalkylcarbonyl,
C.sub.1-10alkylcarbonyl, hetero-arylcarbonyl and ##STR57## wherein
X is hydrogen, benzyl, arylC.sub.2-6alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl, or C.sub.3-8cycloalkylC.sub.1-6alkyl; wherein said
aryl, benzyl, or hetero-aryl is optionally substituted with one or
more substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, or aryl; R.sub.2 is
selected from the group consisting of C.sub.1-6alkyl,
C.sub.3-8cycloalkyl, and aryl wherein said aryl is optionally
substituted with one or more substituents each independently
selected from C.sub.1-6alkyl, C.sub.1-6perfluoroalkyl, halogen,
hydroxy, C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8,
y is 1-9 and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or
alkoxy; R.sub.3 is selected form the group consisting of aryl,
C.sub.3-8cycloalkyl, C.sub.1-6alkyl and hetero-aryl wherein said
aryl or hetero-aryl is optionally substituted with one or more
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.4 is selected form the group consisting of H, aryl,
arylC.sub.2-6alkyl, benzyl, hydroxyC.sub.2-6alkyl C.sub.1-6
perfluoroalkyl, C.sub.3-8cycloalkyl and C.sub.1-6alkyl wherein said
aryl or benzyl is optionally substituted with one or more
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6 perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.5 is H, C.sub.1-6alkyl, or C.sub.3-8cycloalkyl; and with the
proviso that (a) when R.sub.1 and R.sub.4 are phenyl or
4-chlorophenyl, and R.sub.5 is hydrogen then R.sub.2 and R.sub.3
are other than methyl simultaneously; (b) when R.sub.1 is phenyl or
4-chlorophenyl and R.sub.4 and R.sub.5 are hydrogen then R.sub.2
and R.sub.3 are other than methyl simultaneously. or a stereoisomer
or pharmaceutically acceptable salt thereof,
2. The compound according to claim 1 wherein R.sub.1 is selected
from the group consisting of aryl, benzyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl, arylC.sub.1-6alkyl and ##STR58## wherein X is
benzyl; R.sub.2 and R.sub.3 are C.sub.1-6alkyl; and R.sub.5 is
hydrogen or C.sub.1-6alkyl.
3. The compound according to claim 1 wherein R.sub.1 is aryl;
R.sub.2 and R.sub.3 are C.sub.1-6alkyl; R.sub.4 is hydrogen; and
R.sub.5 is hydrogen or C.sub.1-6alkyl.
4. The compound according to claim 3 selected from the group
consisting of: 2'-(2-Fluoro-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
2'-(4-Isopropyl-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 2'-(4-Fluoro-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
5,5'-Dimethyl-2'-(4-trifluoromethyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
5,5'-Dimethyl-2'-(4-methoxy-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 2'-(3-Fluoro-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 2'-(2-Methyl-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
55'-Dimethyl-2'-(4-trifluoromethoxy-phenyl) -2H,
2'H-[3,4']bipyrazolyl-3'-ol, 5,5'-Dimethyl-2'-(4-methyl-phenyl)
-2H, 2'H-[3,4']bipyrazolyl-3'-ol,
5,5'-Dimethyl-2'-(3-methyl-phenyl)-2H, 2'H-[3,4']bipyrazolyl-3'-ol,
5,5'-Dimethyl-2'-(2-ethyl-phenyl)-2H, 2'H-[3,4']bipyrazolyl-3'-ol,
5,5'-Dimethyl-2'-(3,4-dichloro-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 5,5'-Dimethyl-2'-(3-chlorophenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
2'-(4-tert-Butyl-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
5,5'-Dimethyl-2'-(3-trifluoromethyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol, and
5'-Methoxy-5,3'-dimethyl-1'-phenyl-2H,1'H-[3,4']bipyrazolyl.
5. The compound according to claim 1 wherein R.sub.1 is aryl;
R.sub.2 and R.sub.3 are C.sub.1-6alkyl; R.sub.4 is
arylC.sub.2-6alkyl, or benzyl; and R.sub.5 is hydrogen or
C.sub.1-6alkyl.
6. The compound according to claim 5 which is selected from the
group consisting of: 5,5'-Dimethyl-2-phenethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 2-Benzyl-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, and
2-Benzyl-5'-methoxy-5,3'-dimethyl-1-phenyl-2H,1'H-[3,4]bipyrazole,
and 2-(3-Hydroxy-benzyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol.
7. The compound according to claim 1 wherein R.sub.1 is aryl;
R.sub.2 and R.sub.3 are C.sub.1-6alkyl; R.sub.4 is
hydroxyC.sub.2-6alkyl, C.sub.3-8cycloalkyl or C.sub.1-6alkyl and
R.sub.5 is hydrogen.
8. The compound according to claim 7 which is selected from the
group consisting of:
5,5'-Dimethyl-2'-phenyl-2-(2,2,2-trifluoro-ethyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
2-Cyclohexyl-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 2-(2-Hydroxy-ethyl)
-5,5'-dimethyl-2'-phenyl-2H, 2'H-[3,4']bipyrazolyl-3'-ol, and
2,5,5'-Trimethyl-2'-phenyl-2H, 2'H-[3,4']bipyrazolyl-3'-ol.
9. The compound according to claim 1 wherein R.sub.1 is aryl;
R.sub.2 and R.sub.3 are C.sub.1-6alkyl; R.sub.4 is aryl; and
R.sub.5 is hydrogen.
10. The compound according to claim 9 which is selected from the
group consisting of:
2-(4-Methoxy-phenyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol and
2-(4-Fluoro-phenyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol.
11. The compound according to claim 1 wherein R.sub.1 is
arylC.sub.2-6alkyl or benzyl; R.sub.2 and R.sub.3 are
C.sub.1-6alkyl; and R.sub.4 and R.sub.5 are hydrogen.
12. The compound according to claim 11 which is selected from the
group consisting of 5,5'-Dimethyl-2'-phenethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
2'-(3-Hydroxy-benzyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, and 2'-Benzyl-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol.
13. The compound according to claim 1 wherein R.sub.1 is ##STR59##
wherein X is benzyl; R.sub.2 and R.sub.3 are C.sub.1-6alkyl; and
R.sub.4 and R.sub.5 are hydrogen.
14. The compound according to claim 13 which is
2'-(1-Benzyl-piperidin-4-yl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol.
15. The compound according to claim 1 wherein R.sub.1 is
C.sub.3-8cycloalkyl; R.sub.2 and R.sub.3 are C.sub.1-6alkyl; and
R.sub.4 and R.sub.5 are hydrogen.
16. The compound according to claim 15 which is
2'-Cyclohexyl-5,5'-dimethyl-2H-2'H-[3,4]bipyrazolyl-3'-ol.
17. A compound which is
5,1',5'-trimethyl-2'-phenyl-1',2'-dihydro-2H-[3,4']bipyrazolyl-3'-one.
18. A pharmaceutical composition comprising an effective amount of
a compound according to claim 1 and a pharmaceutically acceptable
carrier.
19. A method of treating a neuropsychiatric disorder responsive to
modulation of AMPA and NMDA receptors, comprising administering to
a mammal in need of said treatment a therapeutically effective
amount of a compound of formula I ##STR60## wherein: R.sub.1 is
selected from the group consisting of aryl, benzyl,
C.sub.3-8cycloalkyl, C.sub.1-10alkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, hetero-aryl, arylcarbonyl,
arylC.sub.1-6alkylC.sub.3-8cycloalkylcarbonyl,
C.sub.1-10alkylcarbonyl, hetero-arylcarbonyl and ##STR61## wherein
X is hydrogen, benzyl, arylC.sub.2-6alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl, or C.sub.3-8cycloalkylC.sub.1-6alkyl; wherein said
aryl, benzyl, or hetero-aryl is optionally substituted with one or
more substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, or aryl; R.sub.2 is
selected from the group consisting of C.sub.1-6alkyl,
C.sub.3-8cycloalkyl, and aryl wherein said aryl is optionally
substituted with one or more substituents each independently
selected from C.sub.1-6alkyl, C.sub.1-6perfluoroalkyl, halogen,
hydroxy, C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8,
y is 1-9 and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or
alkoxy; R.sub.3 is selected form the group consisting of aryl,
C.sub.3-8cycloalkyl, C.sub.1-6alkyl and hetero-aryl wherein said
aryl or hetero-aryl is optionally substituted with one or more
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.4 is selected form the group consisting of H, aryl,
arylC.sub.2-6alkyl, benzyl, hydroxyC.sub.2-6alkyl
C.sub.1-6perfluoroalkyl, C.sub.3-8cycloalkyl and C.sub.1-6alkyl
wherein said aryl or benzyl is optionally substituted with one or
more substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.5 is H, C.sub.1-6alkyl, or C.sub.3-8cycloalkyl. or a
stereoisomer or pharmaceutically acceptable salt thereof
20. The method according to claim 19 wherein said neuropsychiatric
disorder is selected from the group consisting of depression,
epilepsy, schizophrenia, Alzheimer's, disease, learning and memory
disorders; and mild cognitive impairment.
21. The method according to claim 20 wherein said disorder is
schizophrenia.
22. The method according to claim 20 wherein said disorder is
depression.
23. The method according to claim 20 wherein said disorder is
learning and memory disorders.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of International Patent
Application No. PCT/US2006/009348 filed on Mar. 15, 2006 which is
incorporated herein by reference in its' entirety which also claims
the benefit of priority of U.S. Provisional Application No.
60/662,165 filed on Mar. 16, 2005.
FIELD OF THE INVENTION
[0002] The present invention relates to novel dipyrazole compounds,
compositions, and methods for the treatment and/or prevention of
neuropsychiatric disorders that result primarily from dysfunction
at the glutamate receptors AMPA and NMDA.
BACKGROUND OF THE INVENTION
[0003] Glutamate is the most abundant excitatory neurotransmitter
in the mammalian central nervous system (CNS) and mediates the fast
and slow neurotransmission responsible for such normal
neurophysiological processes as memory acquisition and processing,
and synaptic plasticity. Postmortem and pharmacological findings
strongly implicate dysregulation of glutamate neurotransmission in
the pathophysiology of several neuropsychiatric disorders including
schizophrenia, Alzheimer disease, Parkinson disease, Huntington
disease, epilepsy, attention-deficit hyperactivity disorder,
AIDS-related dementia, neuropathic pain, depression, mild cognitive
impairment, learning and memory disorders, and others (Lehohla, et
al., Metab Brian Dis, 2004; Coyle, et al., Ann. NY Acad. Sci.,
2003; Coyle, et al., Curr. Drug Targets CNS Neurol. Disord., 2002;
Krystal, et al., Arch Gen Psychiatry, 2002; Dingledine et al.,
Pharmacol. Rev., 1999; and Ozawa, et al., Prog. Neurobiol.,
1998).
[0004] Glutamate neurotransmission is mediated by three ionotropic
glutamate receptors. These receptors are cation-specific ion
channels which regulate fast synaptic neurotransmission. The
ionotropic glutamate receptors have been classified into three
types: the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
(AMPA) receptors, the kainic acid (KA) receptors, and the
N-methyl-D-aspartate (NMDA) receptors based on their unique
pharmacological, electrophysiological and biochemical properties
(Nakanishi, Science, 1992). Furthermore, each of these ionotropic
glutamate receptors is made up of multiple heteromeric subunits,
contributing to receptor heterogeneity in different tissues (Ozawa,
et al., Prog Neurobiol, 1998). However, each of the ionotropic
glutamate receptors contain predominant subunits, some requisite
for functionality and thought to be most responsible for the
regulation of function.
[0005] Regulation of the ionotropic glutamate receptors is partly
achieved through phosphorylation of specific tyrosine, threonine
and serine residues by several kinases and, conversely, through
de-phosphorylation of those residues by specific phosphatases
(Carvalho, et al., Neurochem. Res., 2000 and Swope, et al., Adv
Second Messenger Phosphoprotein Res. 1999). The phosphorylation
state of receptor subunits plays a critical role in receptor
activity. For example, NMDA receptors are regulated by several
kinases and phosphatases acting on its NR1 subunit. Protein kinase
C (PKC), and cAMP-dependent protein kinase (PKA) have been shown to
phosphorylate serine residues 896 and 897 of the NR1 subunit,
respectively (Tingley, et al., J. Biol. Chem., 1997 and Snyder, et
al., Neuropharmacology, 2003). Likewise, AMPA receptors are
regulated by several kinases and phosphatases acting on the GluR1
subunit; PKA phosphorylates serine residue 845 (Roche, et al.,
Neuron 16: 1179-1188, 1999; Wang, et al., Science 253: 1132-1135,
1991). Protein phosphatase I (PP1) dephosphorylates these serine
residues, thus leading to a molecular switch for receptor
activity.
[0006] Spinophilin (also named Neurabin II) is a scaffold protein,
which is enriched in the dendritic spines of CNS neurons that serve
as the major site of glutamatergic synapses in the brain (Allen, et
al., Proc. Natl. Acad. Sci. USA, 1997; Hsieh-Wilson, et al.,
Biochemistry, 1999). Spinophilin was originally identified based on
its ability to bind F-actin and protein phosphatase I (PP1). The
interaction of spinophilin with PP1 is especially important for the
function of ionotropic glutamate receptors as spinophilin acts as a
modulator of glutamatergic synaptic neurotransmission by regulating
PP1's ability to dephosphorylate the ionotropic glutamate receptors
via localization. Evidence for such a function has been
demonstrated using voltage whole-cell recordings of kainic
acid-induced rundown of AMPA currents in individual acutely
dissociated prefrontal cortical neurons (Yan, et al., Nature
Neurosci. 1999). In these experiments, agonist-induced rundown of
kainic-acid-evoked currents was inhibited by a peptide
corresponding to the PP1 binding domain of spinophilin, but not by
the same peptide containing a point mutation, thus indicating that
when spinophilin no longer interacts with PP1, AMPA receptors (in
this example) are no longer dephosphorylated to reduce function;
therefore, they remain more active.
[0007] In order to discover small molecule compounds that would
mimic the action of the spinophilin peptide described above, a
novel protein interaction assay between PP1 and spinophilin was
utilized to discover inhibitors of binding. These compounds were
then evaluated in a whole-cell voltage clamp assay for the ability
to inhibit the agonist-induced rundown of AMPA currents and for
modulation of NMDA-evoked currents.
[0008] Thus, compounds discovered here should have utility in the
treatment of several neurospychiatric disorders which have been
linked to the dysfunction of glutamate neurotransmission.
SUMMARY OF THE INVENTION
[0009] The present invention is a compound of formula I: ##STR2##
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein: R.sub.1 is selected from the group consisting of aryl,
benzyl, C.sub.3-8cycloalkyl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.1-6alkyl, hetero-aryl, aryl-carbonyl,
arylC.sub.1-6alkyl-C.sub.3-8cycloalkylcarbonyl,
C.sub.1-10alkylcarbonyl, hetero-arylcarbonyl and ##STR3## [0010]
wherein X is hydrogen, benzyl, arylC.sub.2-6alkyl,
C.sub.3-8cycloalkyl, C.sub.1-10alkyl, or
C.sub.3-8cycloalkylC.sub.1-16alkyl; wherein said aryl, benzyl, or
hetero-aryl is optionally substituted with one or more substituents
each independently selected from the group consisting of
C.sub.3-8cycloalkyl-C.sub.1-6alkyl C.sub.1-6alkyl, C.sub.1-6
perfluoroalkyl, halogen, hydroxy, C.sub.nH.sub.xF.sub.y-6alkoxy
wherein n is 1-4, x is 0-8, y is 1-9 and x+y is 2n+1,
C.sub.1-C.sub.6alkoxy, nitro, or aryl; R.sub.2 is selected from the
group consisting of C.sub.1-6alkyl, C.sub.3-8cycloalkyl, and aryl
wherein said aryl is optionally substituted with one or more
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6 perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.3 is selected form the group consisting of aryl,
C.sub.3-8cycloalkyl, C.sub.1-6alkyl and hetero-aryl wherein said
aryl or hetero-aryl is optionally substituted with one or more
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.4 is selected form the group consisting of H, aryl,
arylC.sub.2-6alkyl, benzyl, hydroxyC.sub.2-6alkyl
C.sub.1-6perfluoroalkyl, C.sub.3-8cycloalkyl and C.sub.1-6alkyl
wherein said aryl or benzyl is optionally substituted with one or
more substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.5 is H, C.sub.1-6alkyl, or C.sub.3-8cycloalkyl; and with the
proviso that [0011] (a) when R.sub.1 and R.sub.4 are phenyl or
4-chlorophenyl, and R.sub.5 is hydrogen, then R.sub.2 and R.sub.3
cannot be simultaneously methy [0012] (b) when R.sub.1 is phenyl or
4-chlorophenyl and R.sub.4 and R.sub.5 are hydrogen then R.sub.2
and R.sub.3 are other than methyl simultaneously.
[0013] The present invention is also directed to pharmaceutical
compositions of formula (I).
[0014] Another aspect of this invention is disclosed a method of
treating a neuropsychiatric disorder responsive to modulation of
AMPA and NMDA receptors, comprising administering to a mammal in
need of said treatment a therapeutically effective amount of a
compound of formula I ##STR4## or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein: R.sub.1 is
selected from the group consisting of aryl, benzyl,
C.sub.3-8cycloalkyl, C.sub.1-10alkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, hetero-aryl, arylcarbonyl,
arylC.sub.1-6alkylC.sub.3-8cycloalkylcarbonyl,
C.sub.1-10alkylcarbonyl, hetero-arylcarbonyl and ##STR5## [0015]
wherein X is hydrogen, benzyl, arylC.sub.2-6alkyl,
C.sub.3-8cycloalkyl, C.sub.1-10alkyl, or
C.sub.3-8cycloalkylC.sub.1-6alkyl; wherein said aryl, benzyl, or
hetero-aryl is optionally substituted with one or more substituents
each independently selected from C.sub.1-6alkyl, C.sub.1-6
perfluoroalkyl, halogen, hydroxy, C.sub.nH.sub.xF.sub.y-6alkoxy
wherein n is 1-4, x is 0-8, y is 1-9 and x+y is 2n+1,
C.sub.1-C.sub.6alkoxy, nitro, or aryl; R.sub.2 is selected from the
group consisting of C.sub.1-6alkyl, C.sub.3-8cycloalkyl, and aryl
wherein said aryl is optionally substituted with one or more
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.3 is selected form the group consisting of aryl,
C.sub.3-8cycloalkyl, C.sub.1-6alkyl and hetero-aryl wherein said
aryl or hetero-aryl is optionally substituted with one or more
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.4 is selected form the group consisting of H, aryl,
arylC.sub.2-6alkyl, benzyl, hydroxyC.sub.2-6alkyl C.sub.1-6
perfluoroalkyl, C.sub.3-8cycloalkyl and C.sub.1-6alkyl wherein said
aryl or benzyl is optionally substituted with one or more
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.5 is H, C.sub.1-6alkyl, or C.sub.3-8cycloalkyl.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The terms as used herein have the following meanings:
[0016] As used herein, the expression "C.sub.1-6 alkyl" used alone
or in combination with other terms means an alkyl (or alkylene as
appropriate), straight or branched-chain and includes methyl and
ethyl groups, and straight-chained or branched propyl, butyl,
pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl,
n-propyl, isopropyl and tert-butyl. Derived expressions such as
"C.sub.1-6alkoxy", "C.sub.1-6alkoxyC.sub.1-6alkyl",
"hydroxyC.sub.1-6alkyl", "C.sub.1-6alkylcarbonyl",
"C.sub.1-6alkoxycarbonylC.sub.1-6alkyl", "C.sub.1-6alkoxycarbonyl",
"aminoC.sub.1-6alkyl", "C.sub.1-6alkylcarbamoylC.sub.1-6alkyl",
"C.sub.1-6dialkylcarbamoylC.sub.1-6alkyl" "mono- or
di-C.sub.1-6alkylaminoC.sub.1-6alkyl",
aminoC.sub.1-6alkylcarbonyl", "diphenylC.sub.1-6alkyl",
"phenylC.sub.1-6alkyl", "phenylcarboylC.sub.1-6alkyl" and
"phenoxyC.sub.1-6alkyl" are to be construed accordingly.
[0017] As used herein, the expression "C.sub.2-6alkenyl" includes
ethenyl and straight-chained or branched propenyl, butenyl,
pentenyl and hexenyl groups. Similarly, the expression
"C.sub.2-6alkylnyl" includes ethynyl and propynyl, and
straight-chained or branched butynyl, pentynyl and hexynyl
groups.
[0018] As used herein, the expression "C.sub.1-6 perfluoroalkyl"
means that all of the hydrogen atoms in said alkyl group are
replaced with fluorine atoms. Illustrative examples include
trifluoromethyl and pentafluoroethyl, and straight-chained or
branched heptafluoropropyl, nonafluorobutyl, undecafluoropentyl and
tridecafluorohexyl groups. The derived expression, "C.sub.1-6
perfluoroalkoxy", is to be construed accordingly.
[0019] As used herein, the expression "C.sub.3-8cycloalkyl" means
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl.
[0020] As used herein, the expression
"C.sub.3-8cycloalkylC.sub.1-6alkyl" means that the
C.sub.3-8cycloalkyl as defined herein is further attached to
C.sub.1-6alkyl as defined herein. Representative examples include
cyclopropylmethyl, 1-cyclobutylethyl, 2-cyclopentylpropyl,
cyclohexylmethyl, 2-cycloheptylethyl and 2-cyclooctylbutyl and the
like.
[0021] As used herein "halogen" or "halo" means chloro, fluoro,
bromo, and iodo.
[0022] As used herein the expression "carbamoyl" means an --NC(O)--
group where the radical is bonded at two positions connecting two
separate additional groups.
[0023] As used herein "aryl" represents a carbocyclic aromatic ring
system such as phenyl, biphenyl, naphthyl, anthracenyl,
phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl,
biphenylenyl and the like. Aryl is also intended to include the
partially hydrogenated derivatives of the carbocyclic aromatic
systems enumerated above. Non-limiting examples of such partially
hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl,
1,4-dihydronaphthyl and the like.
[0024] As used herein "hetero-aryl" represents a heterocyclic
aromatic ring system containing one or more heteroatoms selected
from nitrogen, oxygen and sulfur such as furanyl, thiophenyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,
1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,
1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl,
benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl,
benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl,
benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl,
isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,
carbazolyl, azepinyl, diazepinyl, acridinyl and the like.
Hetero-aryl is also intended to include the partially hydrogenated
derivatives of the heterocyclic systems enumerated above.
Non-limiting examples of such partially hydrogenated derivatives
are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl,
oxazolidinyl, oxazolinyl, oxazepinyl and the like.
[0025] As used herein "heterocyclyl" represents a saturated 3 to 8
membered ring containing one or more heteroatoms selected from
nitrogen, oxygen and sulfur. Representative examples are
pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl,
aziridinyl, tetrahydrofuranyl and the like.
[0026] As used herein, "tautomer" or "tautomerism" refers to the
coexistence of two (or more) compounds that differ from each other
only in the position of one (or more) mobile atoms and in electron
distribution, for example, keto-enol tautomers or tautomerism.
[0027] As used herein, `treat` or `treating` means any treatment,
including but not limited to, alleviating symptoms, eliminating the
causation of the symptoms either on a temporary or permanent basis,
or to preventing or slowing the appearance of symptoms and
progression of the named disease, disorder or condition.
[0028] "Therapeutically effective amount" means an amount of the
compound which is effective in treating the named disorder or
condition.
[0029] As used herein, "patient" means any warm blooded animal,
such as for example, rats, mice, dogs, cats, guinea pigs, and
primates such as humans.
[0030] As used herein, the expression "pharmaceutically acceptable
carrier" means a non-toxic solvent, dispersant, excipient,
adjuvant, or other material which is mixed with the compound of the
present invention in order to permit the formation of a
pharmaceutical composition, i.e., a dosage form capable of
administration to the patient. One example of such a carrier is a
pharmaceutically acceptable oil typically used for parenteral
administration.
[0031] The term "pharmaceutically acceptable salts" as used herein
means that the salts of the compounds of the present invention can
be used in medicinal preparations. Other salts may, however, be
useful in the preparation of the compounds according to the
invention or of their pharmaceutically acceptable salts. Suitable
pharmaceutically acceptable salts of the compounds of this
invention include acid addition salts which may, for example, be
formed by mixing a solution of the compound according to the
invention with a solution of a pharmaceutically acceptable acid
such as hydrochloric acid, hydrobromic acid, sulfuric acid,
methanesulfonic acid, 2-hydroxyethanesulfonic acid,
p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic
acid, malic acid, ascorbic acid, succinic acid, glutaric acid,
acetic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid,
hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid,
citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic
acid, malonic acid, carbonic acid or phosphoric acid. The acid
metal salts such as sodium monohydrogen orthophosphate and
potassium hydrogen sulfate can also be formed. Also, the salts so
formed may present either as mono- or di-acid salts and can exist
either as hydrated or can be substantially anhydrous. Furthermore,
where the compounds of the invention carry an acidic moiety,
suitable pharmaceutically acceptable salts thereof may include
alkali metal salts, e.g. sodium or potassium salts; alkaline earth
metal salts, e.g. calcium or magnesium salts; and salts formed with
suitable organic ligands, e.g. quaternary ammonium salts.
[0032] The expression "stereoisomers" is a general term used for
all isomers of the individual molecules that differ only in the
orientation of their atoms in space. Typically it includes mirror
image isomers that are usually formed due to at least one
asymmetric center, (enantiomers). Where the compounds according to
the invention possess two or more asymmetric centers, they may
additionally exist as diastereoisomers, also certain individual
molecules may exist as geometric isomers (cis/trans). It is to be
understood that all such isomers and mixtures thereof in any
proportion are encompassed within the scope of the present
invention.
[0033] As used in the examples and preparations that follow, the
terms used therein shall have the meanings indicated: "kg" refers
to kilograms, "g" refers to grams, "mg" refers to milligrams,
".mu.g" refers to micrograms, "pg" refers to picograms, "mol"
refers to moles, "mmol" refers to millimoles, "nmole" refers to
nanomoles, "L" refers to liters, "mL" or "ml" refers to
milliliters, ".mu.L" refers to microliters, ".degree. C." refers to
degrees Celsius, "R.sub.f" refers to retention factor, "mp" or
"m.p." refers to melting point, "dec" refers to decomposition, "bp"
or "b.p." refers to boiling point, "mm of Hg" refers to pressure in
millimeters of mercury, "cm" refers to centimeters, "nm" refers to
nanometers, "[.alpha.].sup.20.sub.D" refers to specific rotation of
the D line of sodium at 20.degree. C. obtained in a 1 decimeter
cell, "c" refers to concentration in g/mL, "THF" refers to
tetrahydrofuran, "DMF" refers to dimethylformamide, "NMP" refers to
1-methyl-2-pyrrolidinone, "MP-carbonate" refers to a macroporous
polystyrene anion exchange resin that is a resin bound equivalent
to tetraalkylammonium carbonate, "brine" refers to a saturated
aqueous sodium chloride solution, "M" refers to molar, "mM" refers
to millimolar, ".mu.M" refers to micromolar, "nM" refers to
nanomolar, "TLC" refers to thin layer chromatography, "HPLC" refers
to high performance liquid chromatography, "HRMS" refers to high
resolution mass spectrum, "CIMS" refers to chemical ionization mass
spectrometry, "t.sub.R" refers to retention time, "lb" refers to
pounds, "gal" refers to gallons, "L.O.D." refers to loss on drying,
".mu.Ci" refers to microcuries, "i.p." refers to intraperitoneally,
"i.v." refers to intravenously.
[0034] In one aspect of this invention there is disclosed novel
compounds having the general structure as shown in formula I:
##STR6## or a stereoisomer or pharmaceutically acceptable salt
thereof, wherein: R.sub.1 is selected from the group consisting of
aryl, benzyl, C.sub.3-8cycloalkyl, C.sub.1-10alkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, hetero-aryl, arylcarbonyl,
arylC.sub.1-6alkylC.sub.3-8cycloalkylcarbonyl,
C.sub.1-10alkylcarbonyl, hetero-arylcarbonyl and ##STR7## [0035]
wherein X is hydrogen, benzyl, arylC.sub.2-6alkyl,
C.sub.3-8cycloalkyl, C.sub.1-10alkyl, or
C.sub.3-8cycloalkylC.sub.1-6alkyl; wherein said aryl, benzyl, or
hetero-aryl is optionally substituted with one or more substituents
each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, or aryl; R.sub.2 is
selected from the group consisting of C.sub.1-6alkyl,
C.sub.3-8cycloalkyl, and aryl wherein said aryl is optionally
substituted with one or more substituents each independently
selected from C.sub.1-6alkyl, C.sub.1-6perfluoroalkyl, halogen,
hydroxy, C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8,
y is 1-9 and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or
alkoxy; R.sub.3 is selected form the group consisting of aryl,
C.sub.3-8cycloalkyl, C.sub.1-6-alkyl and hetero-aryl wherein said
aryl or hetero-aryl is optionally substituted with one or more
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.4 is selected form the group consisting of H, aryl,
arylC.sub.2-6alkyl, benzyl, hydroxyC.sub.2-6alkyl
C.sub.1-6perfluoroalkyl, C.sub.3-8cycloalkyl and C.sub.1-6alkyl
wherein said aryl or benzyl is optionally substituted with one or
more substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.5 is H, C.sub.1-6alkyl, or C.sub.3-8cycloalkyl; and with the
proviso that [0036] (a) when R.sub.1 and R.sub.4 are phenyl or
4-chlorophenyl, and R.sub.5 is hydrogen then R.sub.2 and R.sub.3
are other than methyl simultaneously; [0037] (b) when R.sub.1 is
phenyl or 4-chlorophenyl and R.sub.4 and R.sub.5 are hydrogen then
R.sub.2 and R.sub.3 are other than methyl simultaneously.
[0038] In a further embodiment of the compound of formula I of this
invention, R.sub.1 is selected from the group consisting of aryl,
benzyl, C.sub.3-8cycloalkyl, C.sub.1-10alkyl, arylC.sub.1-6alkyl
and ##STR8##
[0039] wherein X is benzyl, R.sub.2 and R.sub.3 are C.sub.1-6alkyl
and R.sub.5 is hydrogen or C.sub.1-6alkyl. [0040] In another
embodiment of the compound of formula I of this invention, R.sub.1
is aryl, R.sub.2 and R.sub.3 are C.sub.1-6alkyl, R.sub.4 is
hydrogen, and R.sub.5 is hydrogen or C.sub.1-6alkyl.
[0041] Representative examples of compounds of this embodiment of
the compound of 'formula I are selected from the group consisting
of: 2'-(2-Fluoro-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
2'-(4-isopropyl-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 2'-(4-Fluoro-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
5,5'-Dimethyl-2'-(4-trifluoromethyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
5,5'-Dimethyl-2'-(4-methoxy-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 2'-(3-Fluoro-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 2'-(2-Methyl-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
55'-Dimethyl-2'-(4-trifluoromethoxy-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 5,5'-Dimethyl-2'-(4-methyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 5,5'-Dimethyl-2'-(3-methyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 5,5'-Dimethyl-2'-(2-ethyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
5,5'-Dimethyl-2'-(3,4-dichloro-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 5,5'-Dimethyl-2'-(3-chlorophenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
2'-(4-tert-Butyl-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
5,5'-Dimethyl-2'-(3-trifluoromethyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol, and
5'-Methoxy-5,3'-dimethyl-1'-phenyl-2H,1'H-[3,4']bipyrazolyl. [0042]
In a further embodiment of the compound of formula I of this
invention, R.sub.1 is aryl, R.sub.2 and R.sub.3 are C.sub.1-6alkyl,
R.sub.4 is arylC.sub.2-6alkyl, or benzyl and R.sub.5 is hydrogen or
C.sub.1-6alkyl.
[0043] Representative examples of compounds of this embodiment of
the compound of formula I are selected from the group consisting
of: 5,5'-Dimethyl-2-phenethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, 2-Benzyl-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, and
2-Benzyl-5'-methoxy-5,3'-dimethyl-1'-phenyl-2H,1'H-[3,4']bipyrazole,
and 2-(3-Hydroxy-benzyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol. [0044] In another embodiment of the
compound of formula I of this invention, R.sub.1 is aryl, R.sub.2
and R.sub.3 are C.sub.1-6alkyl, R.sub.4 is hydroxyC.sub.1-6alkyl
C.sub.1-6perfluoroalkyl, C.sub.3-8cycloalkyl or C.sub.1-6alkyl and
R.sub.5 is hydrogen. [0045] Compounds exemplary of this embodiment
of the compound of formula I are selected from the group consisting
of: 5,5'-Dimethyl-2'-phenyl-2-(2,2,2-trifluoro-ethyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
2-Cyclohexyl-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol,
2-(2-Hydroxy-ethyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, and 2,5,5'-Trimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol. [0046] In yet another embodiment of
the compound of formula I of this invention, R.sub.1 is aryl,
R.sub.2 and R.sub.3 are C.sub.1-6alkyl, R.sub.4 is aryl, and
R.sub.5 is hydrogen.
[0047] Representative examples of compounds of this embodiment of
the compound of formula I are selected from the group consisting
of: 2-(4-Methoxy-phenyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol and
2-(4-Fluoro-phenyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol. [0048] In another embodiment of the
compound of formula I of this invention, R.sub.1 is
arylC.sub.2-6alkyl or benzyl, R.sub.2 and R.sub.3 are
C.sub.1-6alkyl, and R.sub.4 and R.sub.5 are hydrogen.
[0049] Representative examples of compounds of this embodiment of
the compound of formula I are selected from the group consisting
of: 5,5'-Dimethyl-2'-phenethyl-2H, 2'H-[3,4']bipyrazolyl-3'-ol,
2'-(3-Hydroxy-benzyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol, and 2'-Benzyl-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol.
[0050] In a further embodiment of the compound of formula I of this
invention, R.sub.1 is ##STR9## wherein X is benzyl, R.sub.2 and
R.sub.3 are C.sub.1-6alkyl, and R.sub.4 and R.sub.5 are
hydrogen.
[0051] A compound exemplary of this embodiment of the compound of
formula I is 2'-(1-Benzyl-piperidin-4-yl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol.
[0052] In another embodiment of the compound of formula I of this
invention, R.sub.1 is C.sub.3-8cycloalkyl, R.sub.2 and R.sub.3 are
C.sub.1-6alkyl, and R.sub.4 and R.sub.5 are hydrogen.
[0053] A compound exemplary of this embodiment of the compound of
formula I is
2'-Cyclohexyl-5,5'-dimethyl-2H-2'H-[3,4]bipyrazolyl-3'-ol.
[0054] In another embodiment of this invention is disclosed a
compound which is
5,1',5'-trimethyl-2'-phenyl-1',2'-dihydro-2H-[3,4']bipyrazolyl-3-
'-one.
[0055] In another embodiment of the present invention is disclosed
a pharmaceutical composition comprising an effective amount of a
compound of formula I and a pharmaceutically acceptable
carrier.
[0056] In still another embodiment of the present invention, is
disclosed a method of treating a neuropsychiatric disorder
responsive to modulation of AMPA and NMDA receptors, comprising
administering to a mammal in need of said treatment a
therapeutically effective amount of a compound of formula I
##STR10## or a stereoisomer or pharmaceutically acceptable salt
thereof, wherein: R.sub.1 is selected from the group consisting of
aryl, benzyl, C.sub.3-8cycloalkyl, C.sub.1-10alkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, hetero-aryl, arylcarbonyl,
arylC.sub.1-6alkylC.sub.3-8cycloalkylcarbonyl,
C.sub.1-10alkylcarbonyl, hetero-arylcarbonyl and ##STR11## [0057]
wherein X is hydrogen, benzyl, arylC.sub.2-6alkyl,
C.sub.3-8cycloalkyl, C.sub.1-10alkyl, or
C.sub.3-8cycloalkylC.sub.1-6alkyl; wherein said aryl, benzyl, or
hetero-aryl is optionally substituted with one or more substituents
each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, or aryl; R.sub.2 is
selected from the group consisting of C.sub.1-6alkyl,
C.sub.3-8cycloalkyl, and aryl wherein said aryl is optionally
substituted with one or more substituents each independently
selected from C.sub.1-6alkyl, C.sub.1-6 perfluoroalkyl, halogen,
hydroxy, C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8,
y is 1-9 and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or
alkoxy; R.sub.3 is selected form the group consisting of aryl,
C.sub.3-8cycloalkyl, C.sub.1-6alkyl and hetero-aryl wherein said
aryl or hetero-aryl is optionally substituted with one or more
substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy;
R.sub.4 is selected form the group consisting of H, aryl,
arylC.sub.2-6alkyl, benzyl, hydroxyC.sub.2-6alkyl
C.sub.1-6perfluoroalkyl, C.sub.3-8cycloalkyl and C.sub.1-6alkyl
wherein said aryl or benzyl is optionally substituted with one or
more substituents each independently selected from C.sub.1-6alkyl,
C.sub.1-6perfluoroalkyl, halogen, hydroxy,
C.sub.nH.sub.xF.sub.y-6alkoxy wherein n is 1-4, x is 0-8, y is 1-9
and x+y is 2n+1, C.sub.1-C.sub.6alkoxy, nitro, aryl, or alkoxy; and
R.sub.5 is H, C.sub.1-6alkyl, or C.sub.3-8cycloalkyl.
[0058] In another embodiment of the method of this invention, said
neuropsychiatric disorder is selected from the group consisting of
depression, epilepsy, schizophrenia, Alzheimer's, disease, learning
and memory disorders; and mild cognitive impairment.
[0059] In a further embodiment of the method of this invention,
said disorder is schizophrenia.
[0060] In yet another embodiment of the method of this invention,
said disorder is depression.
[0061] In still another embodiment of the method of this invention,
said disorder is learning and memory disorder.
[0062] The compounds of the invention may be prepared by the
synthetic routes described below in the Schemes or by other
methods, which may be apparent to those skilled in the art The R
substituents are as identified for formula (I), above unless
otherwise noted. If necessary, in the following synthetic schemes,
reactive functional groups present in the compounds described in
this invention may be protected by suitable protecting groups. The
protecting group may be removed at a later stage of the synthesis.
Procedures for protecting reactive functional groups and their
subsequent removal may be found in T. W. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis, Wiley and Sons, 1991.
##STR12##
[0063] Scheme A shows the synthesis of a compound of formula I
wherein R.sub.4 and R.sub.5 are hydrogen. In StepA1, the
6-substituted pyrone 1, a compound which is either commercially
available or can readily be synthesized by methods well known in
the art (Lokot, et al, Tetrahedron, 55, 4783-4792, 1999), is
reacted with a carboxylic acid chloride, compound 2, in the
presence of a strong organic acid, to give the 3-acylated
derivative 3. Suitable strong organic acids that may be used in the
reaction are for example, a trihaloacetic acid such as
trifluoroacetic acid or a trifluoroalkylsulfonic acid. The reaction
is typically run at temperatures of from 50.degree. C. to the
reflux temperature of the acid.
[0064] In Step A2, compound 3 is reacted with a hydrazine 4 to form
the hydrazone, compound 5. The reaction is typically performed in
an inert organic solvent such as an alcohol, optionally in the
presence of a suitable base if a hydrazine salt is used as a
reactant. Suitable alcohols include methanol, ethanol, isopropanol
or ethylene glycol and suitable bases include alkali carbonates
such as sodium, potassium or cesium carbonates, or resin bound
carbonates such as MP-carbonate. The temperature at which the
reaction can be run is from ambient to the reflux temperature of
the organic solvent.
[0065] As shown in Step A3 the hydrazone, compound 5, can be
converted to the pyrazolyl dione 6 by affecting an intramolecular
cyclization of 5 in the presence of a suitable organic acid such as
acetic, propionic or trifluoroacetic acid. The reaction is
typically run at elevated temperatures from about 50.degree. C. to
the reflux temperature of the organic acid.
[0066] In Step A4, reaction of the dione 6 with hydrazine 7 gives
the desired bipyrazole 8. The reaction is typically run in an inert
organic solvent such as an alcohol at or near the reflux
temperature of the solvent. ##STR13##
[0067] Scheme B illustrates a method that can be used to synthesize
compounds of formula I wherein and R.sub.5 is C.sub.1-6alkyl,
C.sub.3-8cycloalkyl. In Step B1 the unsubstituted ring nitrogen of
the bipyrazole 8 is protected with an alkoxycarbonyl group to give
a mixture of positional isomers, compounds 9 and 10. The reaction
is accomplished by using methods well known in the art for instance
treatment of 8 with t-butylcarbazate can give compound 9. See
Kashuma, et al, Tetrahedron, 54, 14679, 1998.
[0068] In Step B2 the mixture of isomers 9 and 10 are reacted with
an alkylating/cycloalkylating agent 11 wherein Lg is a leaving
group such as halogen, alkylsulfonate or arylsulfonate to produce a
mixture of the O-alkylated compounds 12 and 13 and the N-alkylated
compounds 14 and 15. The reaction can be run in a polar aprotic
solvent such as DMF, DMSO or acetonitrile in the presence of a
suitable base. Suitable bases include the alkaline and alkali
carbonates and bicarbonates such as potassium and sodium carbonate
and bicarbonate. The temperature at which the reaction can be run
is from ambient to the reflux temperature of the organic solvent.
Following workup of the reaction, chromatography on silica gel
gives two separate mixtures. One mixture consists of the
O-alkylated compounds 12 and 13 the other consists of N-alkylated
compounds 14 and 15.
[0069] The O-alkylated target compound 16 can be obtained as
depicted in StepB3 by cleavage of the N-alkoxycarbonyl from the
positional isomers 12 and 13. The cleavage can be accomplished by
methods that are well known in the art, for example by acid or base
treatment of 12 and 13.
[0070] Similarly, StepB4 employs identical conditions as Step B3 to
give the N-alkylated compound 17.
BIOLOGICAL EXAMPLES
[0071] The following test protocols are used to ascertain the
biological properties of the compounds of this invention. The
following examples are being presented to further illustrate the
invention. However, they should not be construed as limiting the
invention in any manner.
Spinophilin/Protein Phosphatase-1 Interaction Assay:
Materials:
[0072] 10.times. stock TBS (Tris-Buffered Saline) is from Bio-Rad.
Spinophilin (6.times.His) and GST-PP1 proteins are cloned,
expressed, and purified in house by protein production. Eu-anti-GST
antibody, DELFIA assay buffer and DELFIA Enhancement solution are
from Wallac (now Perkin Elmer). High binding 384 well plates are
from Greiner.
Methods for ELISA Time-Resolved Fluorescence 384-Well Assay:
[0073] Plates are coated with 50 ul of Spinophilin/TBS solution (50
ug/ml) or 50 ul of TBS buffer (0 control) and incubated overnight @
4.degree. C. Test compounds are prepared and diluted in 96-well
polypropylene plates using a Labsystems Wellpro Liquid Handler.
After washing the plates 3 times with TBS using the Elx-405
(Biotek) plate washer, the compounds are transferred from the
96-well plate to the 384-well plate using a Multimek (Beckman)
liquid handler. GST-PP1, 50 ul (2.5 ug/ml) is then added to the
plate. Plates are incubated for 3-6 h @ room temperature. The
plates are washed 3 times as above and 50 ul of Eu-anti-GST
antibody (.about.50 ng/ml) are added using a Multidrop (Titertek)
module and allowed to incubate for 30 min at room temperature. The
plates are washed 3 times as above and 100 ul of Enhancement
Solution are added with the Multidrop module and allowed to
incubate for 1 h @ room temperature. Plates are read in the Farcyte
(Tecan) Fluorescence reader using Europium setting. Compounds are
evaluated for their ability to inhibit the interaction of
Spinophilin (6.times.His) and GST-PP1 by measuring a reduction in
the fluorescence signal.
Voltage Whole-Cell Recording of AMPA and NMDA Currents in
Prefrontal Cortical Neurons:
Neuronal Acute-Dissociation Method:
[0074] Prefrontal cortical (PFC) neurons from young adult (3-5
weeks postnatal) rats are acutely dissociated using procedures
similar to those described previously (Feng, et al., J Neurosci,
2001; Chen, et al., Proc Natl Acad Sci USA, 2004). After incubation
of brain slices in a NaHCO.sub.3-buffered saline, PFC is dissected
and placed in an oxygenated chamber containing papain (Sigma, 0.8
mg/ml) in HEPES-buffered Hank's balanced salt solution (HBSS,
Sigma) at room temperature. After 40 minutes of enzyme digestion,
tissue is rinsed three times in the low Ca.sup.+2, HEPES-buffered
saline and mechanically dissociated with a graded series of
fire-polished Pasteur pipettes. The cell suspension is then plated
into a 35 mm Lux Petri dish, which is then placed on the stage of a
Nikon inverted microscope.
Whole-Cell Recording of AMPA and NMDA:
[0075] Whole-cell recordings of whole-cell ion channel currents
employ standard voltage clamp techniques (Yan et al., Nat
Neuroscience, 1999; Wang et al., J Neurosci, 2003; Tyszkiewicz et
al., J. Physiol., 2004). The internal solution (inside the patch
pipette) consists of (in mM): 180 N-methyl-d-glucamine (NMG), 40
HEPES, 4 MgCl.sub.2, 0.1 BAPTA, 12 phosphocreatine, 3 Na.sub.2ATP,
0.5 Na.sub.2GTP, 0.1 leupeptin, pH=7.2-7.3, 265-270 mosm/L. The
external solution consists of (in mM): 127 NaCl, 20 CsCl, 10 HEPES,
1 CaCl.sub.2, 5 BaCl.sub.2, 12 glucose, 0.001 TTX, 0.02 glycine,
pH=7.3-7.4, 300-305 mOsm/L. Recordings are obtained with an Axon
Instruments 200B patch clamp amplifier that is controlled and
monitored with an IBM PC running pCLAMP (v. 8) with a DigiData 1320
series interface (Axon instruments). Electrode resistances are
typically 2-4 M.OMEGA. in the bath. After seal rupture to attain
whole-cell recording conditions, series resistance (4-10 M.OMEGA.)
is compensated (70-90%) and periodically monitored. The cell
membrane potential is held at -60 mV.
[0076] The application of KA (200 .mu.M) or NMDA (100 .mu.M, in
Mg.sup.2+-free solution) evokes a partially desensitizing inward
current. KA or NMDA is applied for 2 seconds every 30 seconds to
minimize desensitization-induced decrease of current amplitude.
Drugs are applied with a gravity-fed `sewer pipe` system. The array
of application capillaries (ca. 150 .mu.m i.d.) is positioned a few
hundred microns from the cell under study. Solution changes are
effected by the SF-77B fast-step solution stimulus delivery device
(Warner Instruments). Data are collected with PCLAMP software and
analyzed with AXOGRAPH, KALEIDOGRAPH, and STATVIEW.
[0077] Compounds described herein inhibit the KA-induced rundown of
AMPA current by either stabilizing the agonist-evoked current of
increasing the current. Likewise, compounds described herein
increase the NMDA-evoked current. The minimum effective dose (MED)
was identified by determining the lowest concentration of inhibitor
that was effective in each functional assay.
[0078] The results of these assays are shown in Table I and Table
II. TABLE-US-00001 TABLE I Inhibition of KA-Induced Rundown of AMPA
Current Minimal Effective Example No. Concentration (.mu.M) 4 .sup.
0.1 * 5 .sup. 0.1 * 15 1.0 18 1.0 25 1.0 * Lowest concentration
tested (MED possibly less than 100 nM).
[0079] TABLE-US-00002 TABLE II Increase of NMDA-Evoked Current
Average percent Minimal Effective increase in NMDA EXAMPLE #
Concentration (.mu.M) current (10 .mu.M) 8 1 303% (n = 3 neurons)
18 5 55% (n = 4 neurons)
Porsolt's Forced Swim Test:
[0080] The effects measured in this model have been correlated to
antidepressant efficacy for drugs. The paradigm of this model is
that an effective antidepressant compound will cause a rat to make
greater attempts to escape a water-filled cylinder than a rat given
vehicle only.
[0081] Animals used in this study are non-naive male Sprague Dawley
rats weighing between 225-350 grams. The test apparatus consists of
6 clear PLEXIGLAS.RTM. cylinders 40 cm high.times.19 cm wide.
Cylinders are filled to 18 cm with 25.degree. C. water. Each rat is
placed in a cylinder for a 15-minute training session. Following
either subchronic or acute dosing of either vehicle (0.5%
methylcellulose) or compound, animals are brought back 24 hours
later for a 5-minute test session. These test sessions are
videotaped for later scoring.
[0082] Subchronic dosing consists of administering drug three times
in the 24-hour period between training and testing. The drug is
administered 24 hrs., 5 hrs., and 1 hr. prior to the test session.
Acute dosing consists of administering the drug once, 1 hour prior
to the test session. Scoring is done using a time-sampling computer
program. Every five seconds, animals are rated as demonstrating one
of three behaviors: immobility, mild swim, or climbing. These
sampling scores are then converted into percentages of the test
session.
[0083] It will be appreciated that every suitable combination of
the compounds of the invention with one or more of the
aforementioned compounds and optionally one or more other
pharmacologically active substances is regarded as falling within
the scope of the claims of the present invention. The examples
detailed below are provided to better describe and more
specifically set forth the compounds, processes and methods of the
present invention. It is to be recognized that they are for
illustrative purposes only however, and should not be interpreted
as limiting the spirit and scope of the invention as later recited
by the claims that follow.
Object Recognition Test:
[0084] The object recognition test is a memory test. It measures
the ability of mice (and rats) to differentiate between known and
unknown objects and is therefore suitable for the determination of
the memory-improving action of the compounds according to the
invention.
[0085] The test can generally be carried out as described in the
literature. (Blokland et al. NeuroReport 1998, 9, 4205-4208;
Ennaceur, A., Delacour, J., Behav. Brain Res. 1988, 31, 47-59;
Ennaceur, A., Meliani, K., Psychopharmacology 1992, 109, 321-330;
Prickaerts, et al. Eur. J. Pharmacol. 1997, 337, 125-136).
[0086] In a first passage, a mouse in an otherwise empty,
relatively large observation arena is confronted with two identical
objects. The mouse will extensively examine, i.e. sniff and touch,
both objects. The amount of time the mouse spends with each object
is scored. In a second passage, after an interval of 24 hours, the
mouse is again tested in the observation arena. One of the known
objects is now replaced by a new, unknown object. When a mouse
recognizes the known object, it will especially examine the unknown
object. After 24 hours, a mouse, however, has normally forgotten
which object it has already examined in the first passage, and will
therefore inspect both objects equally intensively. The
administration of a substance having learning- and memory-improving
action will lead to a mouse recognizing the object already seen 24
hours beforehand, in the first passage, as known. It will examine
the new, unknown object in greater detail than the already known
one. This memory power is expressed in a discrimination index. A
discrimination index of zero means that the mouse examines both
objects, the old and the new one, for the same length of time; i.e.
it has not recognized the old object and reacts to both objects as
if they are both unknown and new. A discrimination index of greater
than zero means that the mouse has inspected the new object for
longer than the old one; i.e. the mouse has recognized the old
object.
MK-801-Induced Psychosis Model:
[0087] The non-competitive NMDA receptor antagonist MK-801 induces
stereotypies and hyperactivity in rodents (Contreras et al.,
Synapse 2: 240-243, 1988) by interacting with the NMDA
receptor-associated ion channel. Phencyclidine, which also
interferes with the NMDA receptor, produces psychotic effects in
humans similar in many respects to schizophrenia. These findings
suggest that a deficiency in glutamate transmission may be
responsible in the pathology of schizophrenia (Javitt & Zukin,
Am. J. Psychiatr., 48:1301-1308, 1991). The neuroleptics
haloperidol, clozapine and raclopride are able to reverse the
behavioral changes induced by MK-801 in rats (Carlsson et al.,
Biol. Psychiatr. 46: 1388-1395, 1999). Therefore the MK-801-induced
activity and stereotypies in rats may represent an appropriate
animal model to test the potential efficacy of antipsychotic
drugs.
[0088] Experimental Procedures
[0089] Male Wistar rats, weight 250-300 g are housed 2 per cage on
a 12 h/12 h light dark cycle (lights on at 7.00 a.m.) at a room
temperature of 21.+-0.2.degree. C. for a minimum of 5 days before
testing. All animals are given access to commercial food and tap
water ad libitum.
[0090] On the day of the experiment, rats are treated with
reference drug vehicle, the reference drugs haloperidol or
clozapine, the test compound vehicle, or test compounds. After
administration, the rats are returned to their home cages for 15
minutes. The haloperidol, clozapine, test compound and vehicle
treated animals receive an i.p. injection of 0.3 mg/kg MK-801. The
remaining rats treated with placebo receive a second injection of
vehicle. The standard injection volume is 2.0 ml/kg. After 10
minutes in the home cages, rats are transferred to the test box
(Plexiglas, 29.times.12.times.12 cm), 5 minutes before the
assessment for accommodation. The test box is cleaned with 70%
ethanol before each assessment. Stereotypies, defined as
wall-contacts with the snout, and locomotion, defined as
turn-rounds of 180.degree., are assessed during 5 minute
periods.
Metrazole Potentiation Assay
[0091] Male CD-1 mice (20-30 grams) are used. On the day of
testing, animals are brought to the laboratory and randomly
assigned to groups. For a primary screen, the test compound is
administered intraperitoneally (i.p., 10 ml/kg) to groups of 10
mice 60 minutes prior to challenge with metrazol (55 mg/kg sc).
Post-metrazol administration animals are placed individually into
clear plastic cylinders (12.times.5 inches) and then observed for
clonic seizures. A clonic seizure is defined as a single episode of
clonic spasms of at least 3-second duration. The mice treated with
metrazol are considered "potentiated" when these clonic seizures
occur.
[0092] A dose range is necessary when 50% of the animals
demonstrate potentiation in the primary screen. Test compounds are
tested at the 60-minute pretreatment time using 3 or more doses
with a vehicle control group. The ED50 value is determined by
linear regression. % .times. .times. Rx .times. .times. group - %
.times. .times. vehicle .times. .times. group 100 - % .times.
.times. vehicle .times. .times. group ##EQU1## Supramaximal
Electroshock Assay
[0093] Male CD-1 mice (18-30 g) are used. Drugs are prepared using
distilled water and if insoluble a surfactant is added. Control
animals receive vehicle. Drugs are routinely administered
intraperitoneally. The route of administration may be varied (p.o.,
s.c.). The dosage volume is 10 ml/kg.
[0094] A constant current stimulator, similar to the apparatus
described by Woodbury and Davenport (Arch. Int. Pharmacodyn. 92:
97-107, 1952) delivers a 60 Hz shock of variable current and
duration through corneal electrodes. A 0.3 s, 25 mA shock (50V) is
sufficient to produce extensor tonus in 95% of control mice.
[0095] A compound is considered to give protection if the mouse
does not exhibit extensor tonus. Protection is expressed as
normalized percent inhibition relative to vehicle control. A time
response is carried out using 6 animals per group. Animals are
tested at 30, 60, and 120 min post-drug. Additional time periods
are tested if indicated by previous tests. When peak activity has
been determined, a dose-response is initiated, using 10 animals per
group at that time period. The ED50 and 95% confidence interval are
calculated by computerized probit analysis.
Synthetic Examples
General
[0096] Commercial reagents and solvents are used as received.
.sup.1H NMR spectra are recorded on a Varian MercuryPlus-300 (300
MHz) or Varian Unity Inova (400 MHz) spectrometer as indicated.
Proton chemical shifts are reported in .quadrature. ppm relative to
internal tetramethylsilane (0.0 ppm). MS (LC-MS) data is obtained
using a Micromass LCT time of flight mass spectrometer with
electrospray ionization and 5 min data acquisition time for m/z 100
to 1000. LC (LC-MS) is performed using a Hypersil C18 column
(4.6.times.50 mm, 3.5 with mobile phase of 0.1% TFA in H.sub.2O (A)
and 0.1% TFA in ACN (B) and a gradient of 5% to 100% B over 3 min
followed by 2 min at 100% B. Alternatively, a Platform LC-MS with
electrospray source may be used with a HP1100 LC system running at
2.0 ml/min, 200 .quadrature.L/min split to the ESI source with
inline HP1100 DAD detection and SEDEX ELS detection. A Luna C18(2)
column (30.times.4.6 mm 3 is used with a gradient of 5% to 95% B
over 4.5 min with mobile phase of 0.1% formic acid in H.sub.20 and
0.1% formic acid in ACN (B). HPLC purification is performed on a
Varian ProStar system using a reversed-phase C18 column with a
linear gradient of ACN/H.sub.2O containing 0.1% trifluoroacetic
acid.
Example 1
[0097] ##STR14##
3-Acetyl-4-hydroxy-6-methyl-pyran-2-one
[0098] Dissolve 4-hydroxy-6-methyl-pyran-2-one (12.6 g, 100 mmol)
in trifluoroacetic acid (50 ml). and add 7.8 g (100 mml) of acetyl
chloride dropwise. Heat this mixture at reflux for 5 hours.
Evaporate the reaction mixture under reduced pressure. Add 50 ml of
water, extract with ethyl acetate (50 ml.times.3) and combine the
organic layers. Wash with brine and dry (sodium sulfate).
Chromatograph on silica gel, eluting with chloroform to provide 5.8
g (34.5 mmol) of 3-acetyl-4-hydroxy-6-methyl-pyran-2-one.
[0099] LCMS (M+H): m/z 169, retention time 3.24 min.
Example 2
[0100] ##STR15##
3-{1-[(2-Fluoro-phenyl)-hydrazono]-ethyl}-4-hydroxy-6-methyl-pyran-2-one
[0101] To 2-fluorophenyl hydrazine hydrochloride (0.16 g, 1.0 mmol)
in methanol (8 ml) add MP-carbonate (1.0 g, 3.3 equivalents). Shake
this mixture at room temperature for 1 hour. Filter the resin and
wash with methanol. To the filtrate add (2-fluorophenyl)-hydrazine
(0.134 g, 0.80 mmol). Shake the reaction mixture at room
temperature for 2 hours after which evaporate the solvent under
reduced pressure. Recrystallize the solid from a minimum amount of
methanol and obtain 0.185 g (0.67 mmol) of
3-{1-[(2-fluoro-phenyl)-hydrazono]-ethyl}-4-hydroxy-6-methyl-pyran-2-one.
[0102] LCMS (M+H): m/z 277, retention time 2.74 min.
Example 3
[0103] ##STR16##
1-[1-(2-Fluoro-phenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane--
1,3-dione
[0104] Heat at reflux for 1 hour
3-{1-[(2-fluoro-phenyl)-hydrazono]-ethyl}-4-hydroxy-6-methyl-pyran-2-one
(0.045 g, 0.163 mmol) in acetic acid (0.3 ml). Add heptane (3 ml)
and evaporate the mixture to dryness to give
1-[1-(2-fluoro-phenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-
-1,3-dione (0.045 g, 0.163 mmol). Use this material for the next
step without further purification.
[0105] LCMS (M+H): m/z 277, retention time 2.05 min.
Example 4
[0106] ##STR17##
2'-(2-Fluoro-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0107] Add to
1-[1-(2-fluoro-phenyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-
-1,3-dione (0.045 g, 0.163 mmol) hydrazine hydrate (0.016 g, 0.32
mmol) in ethanol (1.6 ml). Heat the reaction mixture at reflux for
1.5 hours after which evaporate the ethanol. Wash the residue with
dichloromethane to give 2'-(2-fluoroxphenyl) -5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol (0.028 g, 0.102 mmol).
[0108] LCMS (M+H): m/z 273, retention time 2.16 min.
Example 5
[0109] ##STR18##
2'-(4-Chloro-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0110] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 4-chlorophenyl
hydrazine hydrochloride according to the procedure illustrated in
Examples 2, 3 and 4.
[0111] LCMS (M+H): m/z 289, retention time 2.72 min.
Example 6
[0112] ##STR19##
2'-(4-Isopropyl-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0113] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and
4-isopropylphenylhydrazine hydrochloride according to the procedure
illustrated in Examples 2, 3 and 4.
[0114] LCMS (M+H): m/z 297, retention time 2.85 min.
Example 7
[0115] ##STR20##
2'-(4-Fluoro-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0116] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 4-fluorophenyl
hydrazine hydrochloride according to the procedure illustrated in
Examples 2, 3 and 4.
[0117] LCMS (M+H): m/z 273, retention time 2.00 min.
Example 8
[0118] ##STR21##
5,5'-Dimethyl-2'-(4-trifluoromethyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0119] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 4-trifluoromethylphenyl
hydrazine according to the procedure illustrated in Examples 2, 3
and 4.
[0120] LCMS (M+H): m/z 323, retention time 2.88 min.
Example 9
[0121] ##STR22##
2'-Cyclohexyl-5,5'-dimethyl-2H-2' H-[3,4]bipyrazolyl-3'-ol
[0122] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and cyclohexylhydrazine
hydrochloride according to the procedure illustrated in Examples 2,
3 and 4.
[0123] LCMS (M+H): m/z 261, retention time 1.80 min.
Example 10
[0124] ##STR23##
5,5'-Dimethyl-2'-(4-methoxy-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0125] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 4-methoxyphenyl
hydrazine hydrochloride according to the procedure illustrated in
Examples 2, 3 and 4.
[0126] LCMS (M+H): m/z 285, retention time 1.96 min.
Example 11
[0127] ##STR24##
2'-(3-Fluoro-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0128] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 3-fluorophenyl
hydrazine hydrochloride according to the procedure illustrated in
Examples 2, 3 and 4.
[0129] LCMS (M+H): m/z 273, retention time 2.45 min.
Example 12
[0130] ##STR25##
2'-(2-Methyl-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0131] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 2-methylphenyl
hydrazine hydrochloride according to the procedure illustrated in
Examples 2, 3 and 4.
[0132] LCMS (M+H): m/z 269, retention time 1.70 min.
Example 13
[0133] ##STR26##
55'-Dimethyl-2'-(4-trifluoromethoxy-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0134] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and
4-trifluoromethoxyphenyl hydrazine hydrochloride according to the
procedure illustrated in Examples 2, 3 and 4.
[0135] LCMS (M+H): m/z 339, retention time 3.02 min.
Example 14
[0136] ##STR27##
5,5'-Dimethyl-2'-(4-methyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0137] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 4-methyl-phenyl
hydrazine hydrochloride according to the illustrated in Examples 2,
3 and 4.
[0138] LCMS (M+H): m/z 269, retention time 2.44 min.
Example 15
[0139] ##STR28##
5,5'-Dimethyl-2'-(3-methyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0140] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 3-methylphenyl
hydrazine hydrochloride according to the procedure illustrated in
Examples 2, 3 and 4.
[0141] LCMS (M+H): m/z 269, retention time 2.46 min.
Example 16
[0142] ##STR29##
5,5'-Dimethyl-2'-(2-ethyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0143] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 2-ethylphenylhydrazine
hydrochloride according to the procedure illustrated in Examples 2,
3 and 4.
[0144] LCMS (M+H): m/z 283, retention time 2.32 min.
Example 17
[0145] ##STR30##
5,5'-Dimethyl-2'-(3,4-dichloro-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0146] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 3,4-dichlorophenyl
hydrazine hydrochloride according to the procedure illustrated in
Examples 2, 3 and 4.
[0147] LCMS (M+H): m/z 323, retention time 3.04 min.
Example 18
[0148] ##STR31##
5,5'-Dimethyl-2'-(3-chlorophenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0149] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 3-chlorophenyl
hydrazine hydrochloride according to the procedure illustrated in
Examples 2, 3 and 4.
[0150] LCMS (M+H): m/z 289, retention time 2.28 min.
Example 19
[0151] ##STR32##
2'-(4-tert-Butyl-phenyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0152] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and
4-tert-butylphenylhydrazine hydrochloride according to the
procedure illustrated in Examples 2, 3 and 4.
[0153] LCMS (M+H): m/z 311, retention time 2.62 min.
Example 20
[0154] ##STR33##
5,5'-Dimethyl-2'-phenethyl-2H, 2'H-[3,4']bipyrazolyl-3'-ol
[0155] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and phenethylhydrazine
sulfate according to the procedure illustrated in Examples 2, 3 and
4.
[0156] LCMS (M+H): m/z 283, retention time 2.07 min.
Example 21
[0157] ##STR34##
5,5'-Dimethyl-2'-(3-trifluoromethyl-phenyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0158] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 3-trifluoromethylphenyl
hydrazine hydrochloride according to the procedure illustrated in
Examples 2, 3 and 4.
[0159] LCMS (M+H): m/z 323, retention time 2.62 min.
Example 22
[0160] ##STR35##
2'-(1-Benzyl-piperidin-4-yl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0161] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 1-benzylpiperidin-4-yl
hydrazine dihydrochloride according to the procedure illustrated in
Examples 2, 3 and 4.
[0162] LCMS (M+H): m/z 352, retention time 1.52 min.
Example 23
[0163] ##STR36##
2'-(3-Hydroxy-benzyl)-5,5'-dimethyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0164] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and 3-hydrazinomethylphenol
dihydrochloride according to the procedure illustrated in Examples
2, 3 and 4.
[0165] LCMS (M+H): m/z 285, retention time 1.57 min.
Example 24
[0166] ##STR37##
2'-Benzyl-5,5'-dimethyl-2H, 2'H-[3,4']bipyrazolyl-3'-ol
[0167] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and benzylhydrazine
dihydrochloride according to the procedure illustrated in Examples
2, 3 and 4.
[0168] LCMS (M+H): m/z 269, retention time 1.95 min.
Example 25
[0169] ##STR38##
5,5'-Dimethyl-2'-phenyl-2H, 2'H-[3,4']bipyrazolyl-3'-ol
[0170] Prepare the title compound from
3-acetyl-4-hydroxy-6-methyl-pyran-2-one and phenylhydrazine
according to the procedure illustrated in Examples 2, 3 and 4.
[0171] LCMS (M+H): m/z 255, retention time 1.77 min.
Example 26
[0172] ##STR39##
5'-Methoxy-5,3'-dimethyl-1'-phenyl-2H,1'H-[3,4']bipyrazolyl
[0173] ##STR40##
(A)
5'-Hydroxy-5,3-dimethyl-1'-phenyl-1H-[3,4']bipyrazolyl-2-carboxylic
acid tert-butyl ester
(B)
5-Hydroxy-5,3'-dimethyl-1'-phenyl-1H-[3,4']bipyrazolyl-1-carboxylic
acid tert-butyl ester
[0174] To 5,5'-Dimethyl-2'-phenyl-2H, 2'H-[3,4']bipyrazolyl-3'-ol
(0.118 g, 0.457 mmol) (Example 25) in ethanol (4 ml) add tert-butyl
carbazate (0.120 g, 0.914 mmol). Heat at reflux for 1.5 hours,
after which evaporate the ethanol. Chromatography on silica gel,
eluting with 50% ethyl acetate/heptane provides 0.101 g of a
mixture of positional isomers A and B. Use the mixture for the next
step.
[0175] LCMS (M+H): m/z 355, retention time 1.97 min. and 3.24 min.,
respectively. ##STR41##
(C)
5'-Methoxy-5,3'-dimethyl-1'-phenyl-1'H-[3,4']bipyrazolyl-2-carboxylic
acid tert-butyl ester
(D)
5'-Methoxy-5,3'-dimethyl-1'-phenyl-1H-[3,4']bipyrazolyl-1-carboxylic
acid tert-butyl ester
[0176] ##STR42##
(E)
5,1',5'-Trimethyl-3'-oxo-2'-phenyl-2',3'-dihydro-1'H-[3,4']bipyrazolyl-
-2-carboxylic acid tert-butyl ester
(F)
5,1',5'-Trimethyl-3'-oxo-2'-phenyl-2',3'-dihydro-1'H-[3,4']bipyrazolyl-
-1-carboxylic acid tert-butyl ester
[0177] To a mixture of compounds (A) and (B) (0.100 g, 0.282 mmol)
in DMF (5 ml) add NaHCO.sub.3 (0.071 g, 0.845 mmol) and iodomethane
(0.40 g, 2.82 mmol). Stir the mixture at room temperature
overnight. Dilute the reaction mixture with ethyl acetate (25 ml),
wash with water (30 ml.times.5), and dry (sodium sulfate).
Chromatography on silica gel, eluting with 50% ethyl
acetate/heptane provided 0.013 g of O-methylated products ((C) and
(D) LCMS (M+H): m/z 369, retention time 3.30 min.) and 0.012 g of
N-methylated products ((E) and (F), LCMS (M+H): m/z 369, retention
time 2.63 min.). Use the O-methylated products for the next
step.
5'-Methoxy-5,3'-dimethyl-1'-phenyl-2H,1'H-[3,4']bipyrazolyl
[0178] To the mixture of O-methylated products, compounds (C) and
(D) (0.013 g 0.035 mmol), in dichloromethane (1 ml) add
trifluoroacetic acid (1 ml). Stir this mixture at room temperature
for 1 hour, and then evaporate the mixture to dryness. Dilute the
residue with dichloromethane, wash sequentially with water, aqueous
sodium bicarbonate solution, and water. Dry the organic layer
(sodium sulfate) and concentrate to give 0.006 g (0.022 mm0l) of
the title compound.
[0179] LCMS (M+H): m/z 269, retention time 2.83 min.
Example 27
[0180] ##STR43##
5,1',5'-Trimethyl-2'-phenyl-1',2'-dihydro-2H-[3,4']bipyrazolyl-3'-one
[0181] To the mixture of the N-methyl isomers (E) and (F) of
Example 26 (0.012 g, 0.035 mmol) in dichloromethane (1 ml) add
trifluoroacetic acid (1 ml). Stir this mixture at room temperature
for 1 hour, and then evaporate the mixture to dryness. Dilute the
residue with dichloromethane, wash sequentially with water, aqueous
sodium bicarbonate solution, and water. Dry the organic layer
(sodium sulfate) and concentrate to give 0.009 g (0.035 mmol) of
the title compound.
[0182] LCMS (M+H): m/z 269, retention time 2.06 min.
Example 28
[0183] ##STR44##
2-(4-Methoxy-phenyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0184] To (4-methoxyphenyl)-hydrazine hydrochloride (0.083 g, 0.48
mmol) in ethanol (5 ml) add sodium bicarbonate (0.067 g, 0.80 mmol)
after which stir the mixture for 10 min. Add
1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione
(0.103 g, 0.40 mmol. The mixture was heated at reflux for 1.5 hours
after which it was evaporated to dryness. Chromatography on silica
gel, eluting with 50 to 100% ethyl acetate/heptane provided 0.071 g
of the title compound.
[0185] LCMS (M+H): m/z 361, retention time 2.43 min.
Example 29
[0186] ##STR45##
5,5'-Dimethyl-2-phenethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0187] Prepare the title compound from
1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione
and phenethyl hydrazine sulfate according to the procedure of
Example 28.
[0188] LCMS (M+H): m/z 359, retention time 2.55 min.
Example 30
[0189] ##STR46##
2-(4-Fluoro-phenyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0190] Prepare the title compound from
1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione
and 4-fluorophenyl hydrazine hydrochloride according to the
procedure of Example 28.
[0191] LCMS (M+H): m/z 349, retention time 2.48 min.
Example 31
[0192] ##STR47##
5,5'-Dimethyl-2'-phenyl-2-(2,2,2-trifluoro-ethyl)-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0193] Prepare the title compound from
1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione
and 2,2,2-trifluoro-ethyl hydrazine (70% in water) according to the
procedure of Example 28.
[0194] LCMS (M+H): m/z 337, retention time 2.35 min.
Example 32
[0195] ##STR48##
2-Cyclohexyl-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0196] Prepare the title compound from
1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione
and cyclohexylhydrazine hydrochloride according to the procedure of
Example 28.
[0197] LCMS (M+H): m/z 337, retention time 2.50 min.
Example 33
[0198] ##STR49##
2-(3-Hydroxy-benzyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0199] Prepare the title compound from
1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione
and 3-hydroxybenzyl hydrazine dihydrochloride according to the
procedure of Example 28.
[0200] LCMS (M+H): m/z 361, retention time 2.18 min.
Example 34
[0201] ##STR50##
2-(2-Hydroxy-ethyl)-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0202] Prepare the title compound from
1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione
and 2-hydroxy-ethyl hydrazine according to the procedure of Example
28.
[0203] LCMS (M+H): m/z 299, retention time 1.83 min.
Example 35
[0204] ##STR51##
5,5'-Dimethyl-2,2'-diphenyl-2H, 2'H-[3,4']bipyrazolyl-3'-ol
[0205] Prepare the title compound from
1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione
and phenyl hydrazine according to the procedure of Example 28.
[0206] LCMS (M+H): m/z 331, retention time 2.42 min.
Example 36
[0207] ##STR52##
2-Benzyl-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol
[0208] Prepare the compound from
1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione
and benzylhydrazine hydrochloride according to the procedure of
Example 28.
[0209] LCMS (M+H): m/z 345, retention time 2.69 min.
Example 37
[0210] ##STR53##
2,5,5'-Trimethyl-2'-phenyl-2H, 2'H-[3,4']bipyrazolyl-3'-ol
[0211] Prepare the title compound from
1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione
and methylhydrazine according to the procedure of Example 28.
[0212] LCMS (M+H): m/z 269, retention time 2.10 min.
Example 38
[0213] ##STR54##
2-Benzyl-5,1',5'-trimethyl-2'-phenyl-1',2'-dihydro-2H-[3,4']bipyrazolyl-3'-
-one
[0214] To 2-benzyl-5,5'-dimethyl-2'-phenyl-2H,
2'H-[3,4']bipyrazolyl-3'-ol (Example 36, 0.200 g, 0.58 mmol) in DMF
add cesium carbonate (0.944 g, 2.90 mmol), and then iodomethane
(0.823 g, 5.8 mmol). Stir this mixture at room temperature
overnight. Dilute the reaction mixture with ethyl acetate, wash
with water (25 ml.times.5) and dry (sodium sulfate). Chromatograph
on silica gel, eluting with 50-100% ethyl acetate/heptane to
provide 0.045 g of the title compound.
[0215] LCMS (M+H): m/z 359 with retention time 2.84 min.
[0216] The reaction also affords an O-methyl compound. See Example
39 below.
Example 39
[0217] ##STR55##
2-Benzyl-5-methoxy-5,3'-dimethyl-1-phenyl-2H,1'
H-[3,4']bipyrazole
[0218] Isolate the title compound from the chromatography described
in Example 38 to afford 0.033 g of O-methylated isomer.
[0219] LCMS (M+H): m/z 359 with retention time 3.51 min.
* * * * *